This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. 1. To optimize, through analog synthesis, the most promising inhibitors of drug-resistant P. falciparum selected from previously identified antimalarial lead compounds. Based on previous data, the working hypothesis for this aim is that the strategic chemical modification of the novel compounds polysyphorin (IC50 0.9 [unreadable]M) and lansine (IC50 5.8 [unreadable]M) will yield analogs of greater potency and selectivity, in vitro and in vivo, against multidrug-resistant P. falciparum. 2. To identify novel antimalarial and anticancer lead compounds from the endophytic fungi of Hawaii as bioprobes for molecular target validation, as well as candidates for drug development. The working hypothesis for this aim is that endophytes are a promising (but yet untapped) source of new pharmacological entities for interogating the proteome for new disease targets, and for drug development in general. The antimalarial and anticancer properties of the endophytes of noni (Morinda citrifolia) [unreadable]a plant of enduring ethnomedical significance - are currently being investigated.